Pexidartinib (PLX3397) is a new drug for the treatment of tenosynovial giant cell tumor (TGCT). TGCT is a rare tenosynovial tumor. Surgery is the primary treatment for TGCT at present, which may lead to deterioration of dysfunction and serious complications. In addition, as TGCT has multiple types, which generally occur at bone tissue and joints, the emergence of new interventional therapies is urgently needed in the clinically. At present, PLX3397 is in phase III clinical trials and has been granted the breakthrough therapy designation from the US Food and Drug Administration (FDA). The structure of PLX3397 is shown as formula (I).

Polymorph or polymorphism is the property of some molecules or molecular complexes. Polymorphism may result from different molecular packing. Polymorphs of a given compound may have different crystal structures and physical properties, such as solubility, stability, thermal property, mechanical property, purification ability, X-ray powder diffraction, infrared spectroscopy, Raman spectroscopy, and solid-state NMR spectroscopy, etc. One or combination of multiple characterization methods may be used to differentiate different crystalline forms of the same molecule or molecular complexes.
Novel crystalline forms (including anhydrates, hydrates and solvates, etc.) of the active pharmaceutical ingredients may offer better processing and physicochemical properties, such as bioavailability, stability, processability, and purification ability. Some novel crystalline forms may serve as intermediate crystal forms to facilitate solid state transformation to desired forms. Novel crystalline forms of a pharmaceutical compound may improve properties of drug product. Novel polymorphs of raw materials provide more solid forms in the formulation, and this can improve dissolution, improve shelf life, and make it easier to process, etc.
Different crystalline forms of solid chemical drugs, which may have different solubility and stability, can affect the absorption and bioavailability of drugs, and lead to differences in clinical efficacy. The clinical form of PLX3397 is monohydrochloride. WO2016179415 first disclosed the crystalline forms of PLX3397 monohydrochloride, including Form A, Form B, Form C and Form D. Form A converted to Form C after stored at 80° C. for 7 days. Form B is not a crystalline form in which Form C is mixed. Form D is a methanol solvate. Form A, B and D are not suitable for drug products development. Form C is the only crystalline form suitable for drug development.
Therefore, it is necessary to carry out a comprehensive systematic polymorph screening of PLX3397, and select more crystalline forms with beneficial properties for drug product development.
The inventors of the present disclosure surprisingly discovered a novel crystalline form of PLX3397 monohydrochloride and a novel crystalline form of PLX3397 dihydrochloride during the research process. The crystalline forms of PLX3397 hydrochloride provided by the present disclosure have higher solubility, larger particle size, which is beneficial to separation in the subsequent production process, and good stability, especially superior mechanical stability compared to that of prior art crystal forms. These novel crystalline forms provide a better choice for PLX3397 drug products and are of great value for drug development.